REVIEW
published: 30 March 2022
Edited by:
Stephen J. Pandol,
Cedars-Sinai Medical Center,
United States
Reviewed by:
Shin Hamada,
Tohoku University, Japan
Jami Saloman,
University of Pittsburgh, United States
*Correspondence:
Monika Karpińska
m.karpinska568@gmail.com
Specialty section:
This article was submitted to
Gastrointestinal Sciences,
a section of the journal
Frontiers in Physiology
Received: 02 November 2021
Accepted: 04 February 2022
Published: 30 March 2022
Citation:
Karpińska M and Czauderna M
(2022) Pancreas—Its Functions,
Disorders, and Physiological Impact
on the Mammals’ Organism.
Front. Physiol. 13:807632.
doi: 10.3389/fphys.2022.807632
Frontiers in Physiology | www.frontiersin.org
doi: 10.3389/fphys.2022.807632
Pancreas—Its Functions, Disorders,
and Physiological Impact on the
Mammals’ Organism
Monika Karpińska* and Marian Czauderna
The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Warsaw, Poland
This review aimed to analyze the scientific literature on pancreatic diseases (especially
exocrine pancreatic insufficiency). This review also describes the correlation between
the physiological fitness of the pancreas and obesity. The influence of the pancreatic
exocrine function on the development of the organism of adults and adolescents
was also described. The results of piglet studies available in the literature were
cited as an established model used to optimize treatments for pancreatic diseases
in humans. The pancreas has an exocrine and hormonal function. Consequently, it
is one of the key internal organs in animals and humans. Pancreatic diseases are
usually severe and particularly troublesome. A properly composed diet and taken dietary
supplements significantly improve the patient’s well-being, as well as the course of the
disease. Therefore, a diet and a healthy lifestyle positively affect maintaining the optimal
physiological efficiency of the pancreas.
Keywords: pancreas, pancreatic disorders, pancreatic exocrine insufficiency (EPI), obesity, diabetes
INTRODUCTION
The pancreas is a glandular organ that affects the functioning of the entire body. The emerging
pancreatic insufficiency is the inability of the pancreas to biosynthesize and/or secrete digestive
enzymes in an amount sufficient to digest and absorb food components in the intestines.
Insufficiency usually occurs as a result of damage to the pancreas, which can be caused by a variety
of clinical conditions, e.g., recurrent acute pancreatitis, chronic pancreatitis, diabetes, autoimmune
diseases, after pancreatectomy surgery. It happens that such failure is the result of pancreatic or
gastrointestinal cancer. In children, it is most often associated with cystic fibrosis (about 90% of
patients) or a rare genetic disease like Shwachman-Diamond syndrome. Pancreatic insufficiency is
usually manifested by malabsorption, malnutrition, avitaminosis, and weight loss (or failure to gain
weight in children). Treatment is about treating the root cause, preventing further damage to the
pancreas, and relieving symptoms.
In this paper, the authors present the impact of a malfunctioning pancreas on the organisms
of higher mammals. Based on the analysis of the literature, the influence of the pancreatic
exocrine function on the development of the adult and adolescent organism was described.
Individual diseases that directly affect the health of the pancreas are listed and briefly described.
The correlation between pancreatic diseases and factors such as diet, lifestyle, and obesity
was also discussed.
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STRUCTURE OF THE PANCREAS
Anatomically, the pancreas is divided into head, body, and tail
(Figure 1). The pancreatic parenchyma has a lobular structure
and contains numerous secretory vesicles, which make up 80–
85% of the organ’s mass. The discharge ducts are very important
for the functioning of the pancreas. Each bubble has an outgoing
wire that connects to the others and connects to the main duct.
The main duct is the pancreatic duct, which begins in the tail of
the pancreas, runs the entire length of the organ, and eventually
enters the duodenum through the greater papilla (Vatera). Apart
from it, there is also the accessory pancreatic duct, which in about
70% of people connects to the pancreatic duct, and finally, the
substance secreted by the pancreas, transported through both
ducts, goes to the so-called greater duodenal papilla. In the
histological structure of the pancreas, two basic elements are
distinguished: pancreatic islets (or Langerhans islands – their
number may even reach 2 million and they produce pancreatic
hormones) and secretory cells, which constitute the rest of the
organ and are responsible for the secretion of pancreatic juice and
pancreatic enzymes.
PHYSIOLOGICAL FUNCTIONS OF THE
PANCREAS
The pancreas has two essential and very important functions in
the body: endocrine (production of hormones that regulate blood
sugar levels and glandular secretion) and exocrine (the function
of the digestive gland) (Yamada et al., 2005). Endocrine activity is
performed by the Langerhans islets and involves the production
of hormones such as insulin, proinsulin, amylin, C-peptide,
somatostatin, pancreatic polypeptide (PP), and glucagon. Insulin
helps to lower blood sugar, and glucagon causes blood sugar
to rise. On the other hand, the exocrine activity consists of
the production of enzymes that are part of the iso-osmotic,
alkaline pancreatic juice and support the digestion of food
in the intestines. The intravesical cells produce the enzymatic
components of the juice, which is led into the duodenum
through the pancreatic ducts. In addition, mucus is secreted
in the pancreatic ducts through goblet cells. The composition
of pancreatic juice includes enzymes that digest proteins, fats,
carbohydrates, and nucleic acids, as well as electrolytes and a
small amount of mucus (Dabrowski
˛ et al., 2007).
Enzymes such as trypsin, chymotrypsin, carboxypeptidase,
and elastase belong to the group of proteolytic enzymes
(they digest proteins). Trypsin and chymotrypsin are secreted
in the form of proenzymes: trypsinogen, chymotrypsinogen.
The pancreatic lipolytic enzymes are lipase, phospholipase,
and esterase, which digest fats. The glycolytic (carbohydrate
digesting) enzymes are lactase and amylase, which breaks
down starch into maltose, maltotriose, and dextrins. Nucleolytic
enzymes include ribonuclease and deoxyribonuclease, which
break down nucleic acids into mono- and oligonucleotides. Food
consumption and the neurohormonal mechanism regulate the
secretion of digestive enzymes. The pancreas secretes pancreatic
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Exocrine Pancreas Physiology and Pathophysiology
juice in a volume of about 1–4 liters per day, and this amount
depends on the food consumed.
INFLUENCE OF THE EXOCRINE
FUNCTION OF THE PANCREAS ON THE
DEVELOPMENT OF THE ADULT AND
ADOLESCENT ORGANISM
The central nervous system and hormones regulate the
exocrine function of the pancreas. Hormones such as secretin
and cholecystokinin (CCK) are believed to be the main
intestinal hormones that regulate the secretion of pancreatic
digestive enzymes (Morisset, 2020). Secretin is released from
enteroendocrine cells in the small intestine, and CCK is released
from the duodenum and jejunum in the presence of lipids and
proteins from ingested food. Kapica et al. (2018) described the
effect of obestatin (a hormone produced in specialized cells in the
gastric and small intestine of many animals, including humans)
on the exocrine pancreatic secretion in rats. They found that this
hormone can stimulate the secretion of pancreatic juice through
two opposing mechanisms.
For a long time, scientists have been trying to better
understand the impact of the physiological functions of the
pancreas on the human body. The recognized model closest
to humans is the pig model. CCK has also been shown to be
the main regulator of the exocrine function of the pancreas in
pigs, despite the lack of CCK receptors (Schweiger et al., 2000;
Morisset et al., 2003). It has also been observed that pancreatic
development in pigs appears to be more dependent on diet
change at weaning than on age (Pierzynowski et al., 1993). The
consumption of milk by a piglet causes a postprandial rise in
glucose, but not in insulin (Pierzynowski et al., 1995). Therefore,
it can be concluded that milk can regulate the exocrine function
of the pancreas by producing the amount and type of enzymes
needed for digestion. In the available literature, some reports
indicate a positive correlation between the exocrine function
of the pancreas and weight gain in both suckling piglets (van
den Borne et al., 2007) and in young piglets (Botermans and
Pierzynowski, 1999; Pierzynowski et al., 2005). Pierzynowski et al.
conducted an experiment on piglets, in which in 7 out of 10 pigs
tested, with increasing body weight, they observed an increase in
exocrine pancreatic secretion and a higher exocrine pancreatic
secretion after a meal than preprandial secretion (Flegal et al.,
2010). Disturbances in digestion and feed absorption in pigs
with EPI result in slower growth of the animal. However, as pigs
age, the impact of the pancreatic exocrine function on organism
growth decreases. Gregory et al. found that in pigs of ∼ 30 kg
body weight, EPI causes complete stunting (Gregory et al., 1999),
and Corring and Bourdon (1977) only observed a 25% growth
retardation in pigs ligated at 40 kg. Pierzynowski et al. (1990)
conducted studies on the development of pancreatic exocrine
function in piglets. The experiment consisted in monitoring
gastric secretion and the excretion of total protein and trypsin
before and after feeding during the 1st 13 weeks of animal life
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FIGURE 1 | General diagram of the human pancreas (shutterstock).
(Pierzynowski et al., 1990). The results of the studies showed
that the basal pancreatic function and secretory response to
feeding remained low until 4–5 weeks of age. Only after weaning
the piglets, both the secretion of pancreatic juice and the
secretion and activity of trypsin increased significantly. It was
also observed that the enzymatic composition of pancreatic juice
changed qualitatively during this period. Moreover, intravenous
administration of cholecystokinin (CCK) and secretin did not
stimulate exocrine function during the 1st 2 weeks of age, while
a significant effect was observed from 3 to 4 weeks of age.
Thus, during individual development, they found an increase
in the exocrine pancreatic function and a qualitative change
in the pattern of hydrolytic enzymes. They also observed an
increase in the pancreatic response to hormonal stimulation
during the feeding period.
Fedkiv et al. (2009) investigated the growth performance of
pigs with exocrine pancreatic insufficiency (EPI) at different ages.
They subjected the experiment to twelve 7-week-old weaners and
twelve 16-week-old pigs during the fattening period. Six pigs
from each group underwent surgery for ligation of the pancreatic
duct. They monitored the growth of the animals and recorded
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Exocrine Pancreas Physiology and Pathophysiology
the consumption of porcine pancreatin enriched feed (Creon R
10000). They observed that EPI caused growth inhibition in
weaner pigs but did not affect the growth of older pigs compared
to the corresponding unoperated groups of pigs. Older pigs
subjected to the experiment showed the ability to adapt to EPI
without apparent negative effects on their growth. In addition,
pancreatin feed supplementation has been shown to increase feed
consumption (i.e., improve appetite) in both pigs with EPI and
non-operated pigs.
In another experiment, Rothenbacher et al. measured the
amount of pancreatic elastase-1 in their stools in a large group
of older people (i.e., 914 people aged 50–75. In this group,
11.5% of respondents showed signs of EPI, and signs of severe
exocrine pancreatic insufficiency (SEPI) were shown by 5.1% of
surveyed people (Rothenbacher et al., 2005). The incidence of
both diseases was greater in men than in women. Researchers
found a marked increase in EPI and SEPI with the age of patients.
Then, the influence of various factors on the occurrence of EPI
and SEPI was analyzed. It was found that those consuming less
alcohol had the lowest incidence of both diseases (EPI 7.4%,
SEPI 3.1%) than those reporting higher alcohol consumption
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(EPI 13.4%, SEPI 5.4%), although the differences among levels of
alcohol consumption were not statistically significant (P > 0.05).
Similarly, cigarette smoking resulted in a higher incidence of
EPI and SEPI, while body mass index, diabetes, history of
gallstones, or cholecystectomy showed no statistically significant
(P > 0.05) association with EPI and SEPI. The occurrence of
hyperlipidemia was associated with a lower incidence of both
EPI and SEPI. Subsequently, several drugs suspected of being
associated with pancreatitis and EPI and SEPI were analyzed.
It has been observed that in patients receiving angiotensin-
converting enzyme (ACE) inhibitors, the incidence of EPI and
SEPI was significantly lower than in patients without this drug.
For several years, researchers have been looking for a
way to improve the quality of life and health of patients
with EPI. Research has been conducted on the use of
microbial pancreatic enzymes in pigs to investigate intestinal
regeneration and the effectiveness of microbial pancreatic
enzyme supplementation on pig performance (Pierzynowski
et al., 2012). This supplementation increased the fat and nitrogen
absorption coefficient and contributed to an increase in the
activity of lipase, amylase, and proteolytic activity, although the
values of these coefficients were still lower than in healthy pigs.
PANCREATIC EXOCRINE
INSUFFICIENCY
Exocrine pancreatic insufficiency (EPI) causes problems with the
digestion of food. EPI prevents the pancreas from producing
enough pancreatic enzymes to help the body break down and
absorb nutrients. The body cannot efficiently digest and absorb
fats, proteins, carbohydrates and vitamins and minerals in
food. The damage to the pancreas causing EPI can occur as a
result of factors such as: chronic pancreatitis, pancreatic, gastric,
or intestinal surgery, cystic fibrosis, Shwachman-Diamond
syndrome. Crohn’s disease and celiac disease can also lead to EPI
in some people. Also, excessive alcohol consumption is one of the
leading causes of chronic pancreatitis. It has been assumed that
about 6–12 years of heavy drinking (>80 g of ethanol per day)
contributes to the development of chronic pancreatitis caused by
alcohol (Dufour and Adamson, 2003). Clinical studies on diabetic
patients confirm that this group is particularly susceptible to EPI
(Hardt et al., 2000, 2003).
Exocrine pancreatic insufficiency may be asymptomatic
initially, but when the damage to the pancreas begins to reduce
the capacity to absorb fat, symptoms such as abdominal pain or
tenderness, diarrhea, gas, or a feeling of fullness may occur. You
can also lose weight and other problems, such as bone pain if
you don’t get enough vitamin D, or you can develop a bleeding
disorder if you are deficient in vitamin K from not absorbing
enough vitamins.
Diagnosis is by taking a blood test to check your body’s
vitamin levels and whether your pancreas is synthesizing enough
enzymes. It is also good to check the patient for signs of a disease
that may lead to EPI (e.g., celiac disease). It may also be necessary
to perform a “3-day stool test,” which allows you to check the
amount of fat in your bowel movements. Tests such as CT scan,
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Exocrine Pancreas Physiology and Pathophysiology
MRI, endoscopic ultrasound are also often performed, which
check whether the pancreas is inflamed.
The main treatment for EPI is pancreatic enzyme replacement
therapy (PERT). It involves taking tablets with meals that replace
the enzymes that the pancreas should produce. These enzymes
break down food, making it easier for the body to digest it and
absorb the enzymatic digestion of proteins and fats contained in
the diet. Sometimes you may also need to take antacids to keep
your stomach from breaking down the pancreatic enzymes before
they start to work. Administration of a pancreatic polypeptide is a
promising new treatment (Ramalho and Dytz, 2020). In addition
to taking medications, symptoms can be relieved by following
a proper diet. It is recommended to eat six small meals and
supplement with vitamins such as A, D, E, and K to replace those
not absorbed from the diet (The National Pancreas Foundation,
2021). Alcohol, which makes it difficult for your body to absorb
the fat in your food, should be avoided.
Unfortunately, identifying and diagnosing EPI can be difficult
as many symptoms overlap with other gastrointestinal disorders.
DISORDERS AFFECTING PANCREATIC
FUNCTIONS
Frequently, patients with exocrine pancreatic insufficiency
develop other conditions associated with digestive problems.
These problems can be both the result of the EPI and its cause
(reason). Sometimes they also overlap with the EPI. Therefore,
it is important to work closely with your doctor to obtain the
correct diagnosis and treatment.
Inflammatory Diseases
Chronic and Acute Pancreatitis
Chronic pancreatitis (CP) is the most common cause of EPI
in adults and the most common pancreatic disease. As a result
of inflammation, the cells in the pancreas stop working as they
should, and the enzymes produced by the pancreas start working
before they reach the small intestine. Inflammation in the gland
disrupts insulin production, and digestive enzymes may even
begin to “digest” the pancreas and surrounding tissues. If left
untreated, chronic pancreatitis (CP) can be fatal. From a clinical
point of view, several different CP subtypes are distinguished
that are well defined in their clinical patterns and morphological
imaging features: autoimmune pancreatitis (Finkelberg et al.,
2006; de Pretis et al., 2018), paraduodenal pancreatitis (Rebours
et al., 2007; de Pretis et al., 2017), pancreatitis associated with gene
mutations (Frulloni et al., 2003, 2008).
Basically, we distinguish between two types of inflammation:
acute and chronic. Their origin may have many reasons. The
risk of inflammation is increased by poor health, genetic
predisposition, but most of all by an improper diet and a
bad lifestyle (Whitcomb et al., 2016). Many factors can lead
to chronic pancreatitis. Some of the most important ones are:
alcohol abuse and smoking (Lin et al., 2000), inflammation
caused by a malfunctioning immune system, as well as high blood
lipids, certain autoimmune disorders, and genetic problems
(Merck Manual, 2021). Occasionally, inflammation can occur
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as a result of certain medications or cancerous changes in the
gland. As with many diseases, chronic stress is also one of the
main causes of inflammation. Over the years, inflammation can
lead to irreversible damage to the pancreas, thereby worsening
the digestive processes and damaging insulin-producing cells,
leading to the onset of diabetes (Lohr et al., 2017). In
addition to digestive system disorders, CP may contribute to
developing other complications (resulting from malnutrition) in
the cardiovascular system, bones and the immune system (Bang
et al., 2014a; Hsu et al., 2016).
Acute pancreatitis occurs unexpectedly without any previous
symptoms. The disease is more common in men and usually
appears between the ages of 30 and 40. Patients typically
complain of lower abdominal and middle back pain, possibly
with vomiting, dizziness and increased sweating. If left untreated,
CP can cause false cysts to form in the glandular tissue.
Once infected, they cause abscesses. In severe cases, there
may be blood poisoning, kidney failure, breathing difficulties;
eventually, the patient may experience shock. In instances of
acute pancreatitis, medications and drips may be necessary.
Painkillers, enzyme supplementation, steroid use or, in the case
of diabetes mellitus, treatment may be contemplated for chronic
inflammation. Diet is necessary for both acute and chronic
pancreatitis. In order for the immune system to be active enough
to fight inflammation, the intestinal flora must be balanced. The
state of the gut flora, otherwise known as the gut microbiome,
directly affects the immune system. Animal studies also show
that angiotensin-converting enzyme (ACE) inhibitors alleviate
chronic pancreatitis and are suggested as a potential treatment
for CP (Kuno et al., 2003).
In some cases, the disease results from an inherited disorder of
the pancreas or gut. Recurrent acute attacks in people under the
age of 30 often turn into a chronic disease. The inherited disease
that most often leads to this inflammation is cystic fibrosis. There
are also cases where the only possible method of diagnosis is
surgery. Hereditary pancreatitis is a progressive disease that may
be associated with pain, diarrhea, malnutrition, or diabetes. There
are few studies on the long-term survival of patients with CP,
and available data indicate that the majority of deaths (60–75%)
are due to extra-pancreatic sequelae and possibly alcohol and
smoking abuse (e.g., lung or esophagal cancer), liver cirrhosis,
and myocardial infarction (Levy et al., 2014). Published studies
showed that tuberculosis, gastrointestinal diseases, malignant
neoplasms and cardiovascular diseases were the most frequently
reported causes of death among CP patients (Yadav et al., 2011;
Bang et al., 2014b).
Celiac Disease
Celiac disease is a chronic inflammatory bowel disease. People
suffering from this condition damage their intestines by
consuming gluten (a protein found in wheat, barley, and rye)
(Celiac Disease Foundation, 2021). Although the pancreatic
exocrine function is normal in this disease, the decreased
level of cholecystokinin release (as a result of duodenal villi
atrophy) contributes to the impaired gallbladder contraction and
reduction of pancreatic function exocrine secretion (Fraquelli
et al., 1999; Deprez et al., 2002). Thus, the pancreas may not
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Exocrine Pancreas Physiology and Pathophysiology
be secreting enzymes properly due to inflammation and damage
to the intestines.
Neoplastic Diseases
Tumors or Cysts
The most serious pancreatic disease is neoplasms, including
endocrine neoplasms (pancreatic neuroendocrine tumors)
and exocrine neoplasms (pancreatic cancer). Neuroendocrine
neoplasms are considered diseases heterogeneous in terms of
clinical and pathological features, which have a relatively slow
clinical course compared to non-endocrine neoplasms (Rinzivillo
et al., 2020). Neuroendocrine tumors (i.e., neuroendocrine
neoplasia – NENs) are characterized by a relatively slow growth
rate and the ability to secrete various peptide hormones and
biogenic amines (Cives and Strosberg, 2018).
Tumors and cysts can cause EPI by blocking the main duct
of the pancreas, where enzymes enter the intestines. Pancreatic
cancer is resistant to many common treatments, including
chemotherapy and radiation therapy. If diagnosed at an early
stage, it can be treated surgically. Unfortunately, early diagnosis
is rare, and at a later stage, one can only try to improve the
patient’s quality of life by treating symptoms and complications
alone. Despite many studies, it is still not fully clear what
causes pancreatic cancer to appear. Factors that may increase
your risk of developing this type of cancer include smoking,
diabetes, obesity, chronic pancreatitis, and some hereditary gene
mutations. Unfortunately, as many as 95% of pancreatic cancer
patients die, even with appropriate treatment.
Pancreatic ductal adenocarcinoma (PDAC) accounts for over
90% of all pancreatic cancers and is the major exocrine tumor
subtype (Gloor et al., 2002; Wang et al., 2020). The tumor’s
unique microenvironment and its aggressive nature make it
poorly responding to conventional chemotherapy, and its poor
prognosis translates into an overall 5-year survival rate of
8.5% (Yamamoto et al., 2015). Studies show that the risk of
developing pancreatic cancer increases significantly in patients
with CP (Hao et al., 2017). Pancreatitis contributes to the
development of tumor initiation and progression, influences
treatment responses, metastasis and prognosis (Shi and Xue,
2019). Patients diagnosed with CP have an eightfold risk of
developing pancreatic cancer 5 years after diagnosis (Kirkegard
et al., 2017). Endoscopic ultrasonography (EUS) is the most
sensitive, non-surgical method helpful in detecting pancreatic
cancer (Luz et al., 2014; Singh and Faulx, 2016).
Pancreatic cysts, in many cases, are detected by computed
tomography or MRI obtained during diagnostic tests for a
completely different reason. Currently, different types of cysts
are diagnosed. Depending on the type of fluid they contain,
they are divided into two main varieties. The most common
cysts are serous (containing a rare type of fluid) or mucous
(containing a thicker, more viscous fluid). Mostly serous cysts
are benign and non-cancerous. Most mucous cysts are also
benign, although several subtypes may be different in nature.
These include: mucinous cystic neoplasm (MCN), which contains
ovarian tissue and occurs in women, and endothelial mucosal
neoplasm of the main duct (IPMN), a type of mucous cyst that
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contains many small projections that cover the main pancreatic
duct (Wu, 2021).
Currently, the only form of cyst treatment is surgery. However,
pancreatic surgery is quite a serious medical undertaking, and
therefore resection is performed only in cases where there is a
serious risk of tumor formation. In the vast majority of cases,
observation with periodic imaging tests is sufficient. Scientists
and physicians are continuing their research to determine
the best observation interval to monitor these cysts. Clinical
studies are also underway to identify more accurate early
markers of malignancy.
Zollinger-Ellison Syndrome
This rare disorder occurs when growing tumors in the pancreas,
duodenum, or part of the small intestine cause the body to release
too much of a hormone called gastrin. This, in turn, causes the
stomach to release too much acid. This disorder can lead to
the appearance of, inter alia, stomach ulcers, abdominal pain,
and diarrhea, but unlike EPI, the most common symptom is a
burning pain between the chest and stomach (National Institute
of Diabetes and Digestive and Kidney Diseases, 2021).
Hereditary Diseases
Cystic Fibrosis
Cystic fibrosis is an inherited disease in which there is damage to
the pancreatic ducts. It is also the second most common cause
of EPI. In patients with cystic fibrosis, pancreatic gland cells
break down and become fibrotic. Thickened mucus accumulates
in the area of the pancreatic ducts. As a consequence, pancreatic
exocrine, and endocrine insufficiency occurs. Adequate nutrition
is important in treating cystic fibrosis and EPI. In these diseases,
the cells of the lungs and digestive system form thick, sticky
mucus, which contributes to the blockage of some organs (Mayo
Clinic, 2021). As a result, the pancreas blocks the passage of
digestive enzymes into the intestines, where they help break down
fats and other nutrients.
Diabetes
Currently, diabetes is the third cause of death in the world after
high blood pressure and smoking. It is estimated that diabetes
affects at least about 8.5% of the population, and this percentage
is growing. In order for the human body to maintain the correct
level of glucose (blood sugar) within a very narrow range, it needs
two hormones: insulin and glucagon, which are secreted by the
pancreas (pancreatic endocrine hormones) (Al-Husseina et al.,
2021). Frequently, damage from chronic pancreatitis also affects
the cells in the pancreas that produce these two hormones. This
leads to the development of type 1 or type 2 diabetes (Hardt
et al., 2008; Wei et al., 2020). Type 1 diabetes mellitus is an
autoimmune disease characterized by the failure of the pancreatic
cells to secrete any insulin and leads to a severe increase in
blood glucose levels, causing long-term complications (Ma et al.,
2018; Turksoy et al., 2018). About 80% of all cases of type 3c
diabetes mellitus are associated with chronic pancreatitis (Ewald
and Hardt, 2013). However, some recent research suggests that
EPI itself can also cause diabetes. The course of the disease is
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Exocrine Pancreas Physiology and Pathophysiology
additionally complicated by comorbidities such as poor digestion
and accompanying qualitative malnutrition.
Scientists trying to explain the frequent occurrence of exocrine
pancreatic insufficiency in diabetes have put forward hypotheses
about the dysregulation of exocrine secretion due to diabetic
neuropathy (Pirart, 1978) and atrophy of exocrine tissue due to
the lack of local trophic action of insulin (Adler and Kern, 1975).
The second issue considered was the simultaneous exocrine and
endocrine dysfunction and autoimmune inflammation caused
by the presence of both specific and exocrine tissue antigens
(Kobayashi et al., 1990; Taniguchi et al., 2003) and genetic defects
of exocrine endocrine cells (Raeder et al., 2006) (possibly caused
by a previous viral or bacterial infection).
Another issue analyzed by the researchers was the assessment
of the role of blood pancreatic amylase in the regulation of
glucose homeostasis and insulin secretion in a porcine model of
streptozotocin- (STZ-) induced diabetes and in a rat pancreatic
beta-cell line, BRINBD11 (Pierzynowska et al., 2020). The study
shown that amylase supplementation significantly decreased both
acute and chronic insulin secretion in the BRIN-BD11 cells.
These data confirm the participation of pancreatic amylase in
glucose absorption/utilization. Moreover, the direct impact of
pancreatic blood amylase on insulin secretion from pancreatic
beta-cells and its interactions with insulin and glucagon secretion
in a porcine model was observed.
Shwachman-Diamond Syndrome
It is an autosomal recessive disease characterized by pancreatic
exocrine insufficiency. The clinical features of Shwachman-
Diamond syndrome (SDS) include neutropenia, anemia, and
thrombocytopenia (Gokce et al., 2013). Other symptoms include
recurrent infection tendencies, skeletal changes, and growth
failure. This syndrome may contribute to the development of
neoplasms in the hematopoietic system (Yamada et al., 2005;
Gokce et al., 2013). People with Shwachman-Diamond syndrome
may not have the cells in their pancreas that make enzymes.
OBESITY
Obesity is defined as excess body weight resulting from
the pathological accumulation of adipose tissue in the body
(Marseglia et al., 2015). The main cause of obesity is the
disturbance of energy metabolism homeostasis, which results in a
positive energy balance leading to weight gain. The World Health
Organization (WHO) perceives obesity as a global epidemic,
which is not only a significant clinical and social problem in
the population of adults, children and adolescents (WHO, 2000;
Bryl et al., 2005). Obesity is one of the most important risk
factors responsible for excessive deaths worldwide (Flegal et al.,
2010; Ahima, 2011; Martinson et al., 2011). Overweight in the
developmental age significantly increases the likelihood of this
condition in later years and increases the risk of numerous
metabolic disorders and negative consequences in adulthood
(Morrison et al., 2008; Spiotta and Luma, 2008; Tsigos et al.,
2009; Joseph et al., 2011). New research and data from insurance
companies show that the health risk of excess fat increases even
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with relatively small body weight gain, not just severe obesity.
The long-term effect of increased body weight at an early age is
the development of many chronic diseases, a reduction in the
quality of life and reduced efficiency of the body in adulthood.
Obesity disease is an unconscious and underdiagnosed disease
with serious health consequences.
Obesity is a growing problem in the modern world. Excess
body weight affects the development of lipid metabolism
disorders, insulin resistance, liver and cardiovascular diseases
(at the background of atherosclerosis), hypertension, and sleep
apnea. The fat tissue accumulated in the body in the area
of the heart, liver, pancreas, and muscles significantly affects
the functioning of these organs and poses a significant threat
to health (Sweeting, 2007). So far, the influence of excess
body weight on the impairment of the exocrine pancreatic
function has not been sufficiently studied. Exocrine insufficiency
is common in people with type 1 diabetes, about 50% and
30 – 50%, and in some studies, even in 80% of people with
type 2 diabetes (Schweiger et al., 2000; Hardt and Ewald,
2011). The carbohydrate disturbances that often accompany
obesity correlate with pancreatic exocrine insufficiency. At the
American Association for Cancer Research conference in Atlanta
(29.03.2019–03.04.2019), it has been shown that overweight and
obesity before the age of 50 is more strongly associated with the
risk of death from pancreatic cancer than excess body weight
later in life. Dr. Eric J. Jacobs et al. analyzed data collected from
nearly one million Americans (aged 30–80, cancer-free) enrolled
in the American Cancer Society II nationwide survey (American
Cancer Society Cancer, 2021). Research carried out in 1982–2014
showed that a higher BMI (Body Mass Index) was associated with
an increased risk of death from pancreatic cancer, and that the
increase in risk was highest in younger Americans with a higher
BMI value. An increase in BMI by five units, i.e., a weight gain
of approx. 14.5 kg for a person with a height of ∼ 170 cm, was
associated with a 25% increase in the risk of cancer in those
who were 30–49 years old at the time of measurement, a 19%
increased risk in people aged 50–59, a 14% increase in risk in
people aged 60–69, and 13% – in people aged 70–89. According to
the researchers, excess body weight may increase the risk of dying
from pancreatic cancer much more than previously thought. And
unfortunately, it is observed that the last generations are entering
the early middle age with a much higher weight than previous
generations. The results obtained clearly suggest that in order
to stop and reverse the increase in the incidence of pancreatic
cancer, one must focus primarily on preventing excessive weight
gain in children and young adults (up to 49 years of age). Besides,
in addition to preventing pancreatic cancer, it will also help
prevent many other diseases (especially civilization diseases).
DIETS
Diet has a huge impact on how a person struggling with
pancreatic diseases feels. When the pancreas does not work
properly, the human body does not receive enough digestive
enzymes to digest and then absorb nutrients from food.
Therefore, malnutrition and/or weight loss that is dangerous to
human health may occur over time. Especially with pancreatitis,
Frontiers in Physiology | www.frontiersin.org
Exocrine Pancreas Physiology and Pathophysiology
a properly composed diet can relieve abdominal pain associated
with this disease. Choosing the right eating plan can put your
pancreas at bay and help it recover. It is extremely important and
even necessary to switch to an appropriate diet when treating or
preventing pancreatic diseases. However, dietary changes do not
affect all patients equally. Therefore, it is important to know what
foods to eat, what to avoid and how these choices can affect the
health of the human body.
A low-fat diet is recommended, which is a modified form
of an easily digestible diet (i.e., a diet high in protein, with
reduced animal fat, and containing antioxidants). A proper daily
energy distribution should consist of: 15% from protein, 20%
from fat and 65% from carbohydrates. At the same time, you must
provide the body with all the necessary nutrients and vitamins.
Recommended fats are mainly vegetable fats: rapeseed and
coconut oil, especially oils rich in omega-3 polyunsaturated fatty
acids (e.g., olive oil or linseed oil). In moderate amounts, you can
use butter 82%. It is necessary to avoid fats containing significant
amounts of unsaturated fatty acids containing a double bond of
trans geometric configuration (except for vaccenic acid). Adding
medium-chain triglycerides – fats derived from coconut oil or
palm kernel oil – can help improve nutrient absorption in chronic
pancreatitis. The available literature confirms the positive effect
of supplementation with omega-6 acids (i.e., conjugated linoleic
acid isomers) on the fatty acid profile in the pancreas and relative
body weight gain (RBWG) of rats (Czauderna et al., 2010).
Due to the limited amount of fat in this diet, deficiencies
of macro and micronutrients and vitamins such as calcium,
magnesium and zinc, as well as A, D, E, K (soluble only in fats),
thiamin and folic acid, may appear (Stigliano et al., 2020). The
deficiency of these substances is associated with an increased
risk of infections (decreased immunity), cardiovascular diseases,
osteoporosis and traumatic fractures (Martínez-Moneo et al.,
2016). Therefore, you should increase the amount of fruit and
vegetables that are rich in carotenoids. These include most
green (i.e., spinach, kale, and lettuce), red and orange (skinless
tomato, pumpkin, carrot, peach, apricot, mango, and melon)
fruits and vegetables. Antioxidant-rich foods such as dark-leaved
vegetables, blueberries, sweet potatoes, grapes, carrots, nuts,
and pomegranates are also beneficial. Antioxidants inactivate
free radicals appearing in the human body; this helps to
reduce the extent of oxidative stress and, at the same time, to
reduce inflammation.
You should also avoid fried or high-fat foods, and foods high
in sugar and spicy foods. Limiting products such as red meat,
offal, French fries and potato chips, mayonnaise, margarine and
butter, cakes, sweetened drinks, and full-fat dairy products is
recommended. These foods are rich in fats and simple sugars that
will increase your triglyceride levels. This increases the amount
of fat in your blood and increases your risk of developing acute
pancreatitis. Research also suggests that processed meat and red
meat increase the risk of pancreatic cancer.
Regularity and the number of meals are very important in this
diet. During the day, it is recommended to regularly eat 4–5 meals
in small portions. An important feature of the menu, taking into
account pancreatic diseases, is the properly balanced distribution
of the proportions between protein, fat, and carbohydrates and
the way of preparing meals. First of all, the food must be cooked
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Karpińska and Czauderna Exocrine Pancreas Physiology and Pathophysiology

in water or steamed. The vegetables are served mostly cooked. adequate nutrition. Eating a diet rich in health-promoting
Only juices and purees are allowed raw. You can also use natural ingredients and replacing pancreatic enzymes with every meal
medicine. A perfect example of this is a decoction of dandelion and snack is very important.
root, which supports the activity of the gallbladder and liver, A properly composed diet, taking into account the condition
which contributes to the regeneration of the pancreas. of the sick person, can significantly affect the well-being and
the course of the disease. Poorly managed diets can lead to
interdependent diseases such as diabetes and can even be life-
LIFE WITHOUT A PANCREAS threatening. A pancreatic friendly diet is rich in lean meat protein
and low in animal fats and simple sugars.
Chronic pancreatitis, emerging tumors (such as adenocarcinoma,
There is a clear relationship between EPI and age and gender
neuroendocrine tumors, duodenal cancer or lymphoma), and
(higher incidence of EPI in men than in women); it can be
hyperinsulinemic hypoglycemia (a state of high insulin levels
assumed that, on average, higher consumption of alcoholic
causing a drop in blood sugar levels) may require surgical
beverages, more frequent smoking of tobacco products and less
removal of the pancreas (pancreatectomy). Since there are other
carefully selected health-promoting diet by men compared to
organs around the pancreas, the surgeon may also remove: the
women are the reasons for these gender differences.
duodenal intestine (the first part of the small intestine), spleen,
Most likely, disorders of digestion and food absorption in
part of the stomach, gallbladder, part of the bile ducts. Living
patients with EPI result in slower growth of the organism, while
without a pancreas is possible, but it requires some important
with age, the influence of exocrine function of the pancreas on
changes. Unfortunately, after surgery to remove this gland, it is
organism growth decreases.
necessary to constantly take medications, including drugs that
replenish pancreatic enzymes and insulin, and it is also necessary
to completely reform the diet.
AUTHOR CONTRIBUTIONS
CONCLUSION MK contributed to the conception and design of the study,
organized the database, and wrote the first draft of the
The pancreas is an internal organ that plays a key role in the manuscript. MC provided consultations on the preparation of the
transformation of essential nutrients that provide energy for cells. work. Both authors contributed to manuscript revision, read, and
Problems with its functioning may negatively affect the health of approved the submitted version.
the human body. Even healthy and relatively young people should
take care of healthy nutrition and an appropriate lifestyle, which
will guarantee optimal pancreatic functioning for many years.
Inappropriate work of the pancreas has a negative impact FUNDING
on the proper functioning of the body, contributing to the
This work has been supported by the National Science Centre:
development of diseases related to the pancreas, as well as
Grant No. 2020/04/X/NZ9/00358 (MINIATURA 4).
obesity. Likewise, leading a wrong lifestyle and poor diet can
cause problems in the proper functioning of this organ. The
mere presence of chronic diseases such as obesity may also be a
contributing factor to the development of pancreatic disorders. ACKNOWLEDGMENTS
Obesity disease is an unconscious and underdiagnosed disease
with serious health consequences. Adequate diet and adherence We would like to thank Frontiers in Physiology for the
to nutritional recommendations, as well as physical activity, experience.
as well as psychological support are also elements of the
therapy. In the treatment of obesity, the most important thing
is to improve the patient’s metabolism, as well as to prevent SUPPLEMENTARY MATERIAL
complications. Obesity is a chronic disease and its treatment
should be permanent. The Supplementary Material for this article can be found
It is possible to manage EPI symptoms by adopting enzyme online at: https://www.frontiersin.org/articles/10.3389/fphys.
substitutes and following a nutritional plan that provides 2022.807632/full#supplementary-material

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